A. Overview and Background of the Institution The Scripps Translational Science Institute (STSI) will integrate the resources and activities of several pre-eminent research, education, and clinical care institutions with the overreaching objective of identifying, inspiring, and nurturing the next generation of clinical and translational scientists, while making groundbreaking scientific discoveries in biomedical research. One of these entities, the Scripps Research Institute (TSRI), which started in 1924, is the nation's largest private not-for-profit biomedical research organization. The mission of TSRI is to make groundbreaking discoveries in the sciences that enable medical and technological innovations of tomorrow, while training versatile and creative scientists for the rapidly evolving future of science. Since the inception of the Ph.D. program in 1989, TSRI has offered students the opportunity to earn a Doctor of Philosophy degree in a fully self-contained curriculum that offers interdisciplinary training outside of the context of discrete scientific departments. Students train amongst a faculty of 221 distinguished scientists including 3 Nobel laureates and 16 members of the U.S. National Academy of Sciences. TSRI provides a discovery-driven research and training environment, with approximately 800 postdoctoral fellows and 250 graduate students who last year published > 1250 scientific research papers. It is not uncommon for graduate students to be mentored by more than one faculty member, one or more senior post-doctoral fellows and graduate students, and staff Ph.D. scientists, all of whom play an integral role in graduate student education. The TSRI Kellogg School of Science and Technology graduate program is consistently ranked in the top 7 in several scientific sub-disciplines, according to the U.S. News & World Report and other similar rankings. TSRI participates in a tetra-instrtutional Medical Scientist Training Program (MTSP) that is centered at the University of California, San Diego. Approximately 10 M.D. /Ph.D. candidates conduct their thesis research at TSRI annually. While there are core curricular tracks in Chemistry, Chemical Biology, Biology, Biophysics and Immunology that serve as pre-defined exemplars, the tradition at TSRI is to customize the curriculum for each student, enabled by the student-to-faculty ratio of approximately 1:1. The TSRI graduate program already has a culture of training students engaged in translational research, enabled by an effective and popular molecular medicine course initiated 3 years ago and numerous faculty who are engaged in this type of research. The ongoing training in translational research will be augmented with a new advanced molecular medicine course, enriching a formal CTSA-associated T32 graduate student curriculum track (comprising two molecular medicine courses and four elective courses) focusing on translational research, and providing a more rigorous mechanism to train the growing number of basic scientists who prefer to engage in translational research. The TSRI infrastructure will also significantly advance current programs focusing on M.D. training in translational science through a CTSA associated K12 program, leading to a Masters of Science degree in Clinical Investigation from the TSRI Kellogg School of Science and Technology, with an optional Ph.D. extension. The TSRI research laboratories and core facilities are located adjacent to the Scripps Clinic and Scripps Green Hospital. In fact, TSRI and Green Hospital share the Stein Clinical Research Building. The Green Hospital is a major teaching hospital of the Scripps Health system, with a large outpatient clinic and home to a full complement of medicine and surgery training programs. An Internal Medicine residency program, comprising 25 clinical trainees, is complemented by clinical fellowship programs in 13 disciplines of medicine and surgery, providing for an additional 35 post-graduate clinical training opportunities each year. Although the numbers of post-graduate trainees may seem smaller than other institutions, the residents and fellows are pre-selected for careers in science. Scripps Clinic itself has a clinical and scientific faculty of over 370 physician and physician-scientists who serve as mentors/teachers for the postgraduate trainees in medicine and surgery. Clinicians at Scripps Clinic are currently conducting over 780 IRB approved clinical trials, often with the involvement of residents and fellows as co-investigators. There are major training programs in two other Scripps Health hospitals. At Scripps Mercy Hospital, the Internal Medicine program has 33 trainees. At Scripps Mercy Chula Vista, the Family Medicine program has 19 residents. The education and career development of all of these physicians-in-training will be integrated into the STSI. All will be eligible to become active participants in the Clinical Scholars programs of the STSI and the new curriculum offered as part of the CTSA Educational programs. The residency and fellowship programs at Scripps Clinic have a long history of promoting engagement in clinical and translational research amongst the trainees. The Internal Medicine Residency Program has required the completion of a clinical or translational research science project as a prerequisite for graduation for more than a decade. The majority of the clinical fellowship programs have established a similar research requirement. These requirements have promoted the spirit of scientific inquiry within the clinical training programs, leading the clinical trainees to produce 44 scientific publications and 83 presented abstracts at scientific meetings in the preceding 2 years. Additionally, the emphasis of these programs on scientific discovery has resulted in a scientific career trajectory for several of the recent graduates of the clinical training programs. For the past several years the senior fellows in Hematology and Oncology, in Allergy and Immunology, and in Rheumatology have devoted the majority of the final one or two years of their fellowship to translational research training. The majority of these trainees have spent at least a year working within TSRI or one of the other STSI-affiliated scientific institutions, such as the Salk Institute and Burnham Research Institute. The Skaggs Clinical Scholar Program was initiated in 1998 to further advance the spirit of scientific inquiry at Scripps Clinic. This program is analogous to a K12 mentored translational science career development program. The Skaggs Clinical Scholar Program, enabled by the generosity of the Skaggs family, has provided substantial seed support for research and up to 80% salary support to train over 30 clinicians in the conduct of clinical/translational research. Each Skaggs Scholar is paired with a full-time faculty member from TSRI who serves as the clinical scholar's mentor. A Table of recent Skaggs Scholars is provided (Supplementary Table 3) highlighting the culture of collaboration amongst clinical and basic scientists to pursue basic science solutions ,to important medical challenges. This K12-like program, which has been in place for nine years, has transformed 80% of the recipients from primarily or exclusively clinical practitioners to true translational scientists, making significant contributions to the mechanistic basis of medicine. This program has also played an important role in transforming the culture at Scripps Health, with a phenotypic switch from pure clinician to physician-investigator that is evident throughout the large multispecialty medical group. Notwithstanding these efforts and accomplishments to promote a culture of physician-investigators, there is considerable room for improvement as explained below. The CTSA support is the ultimate opportunity to build on early successes, formalizing T32 and K12 programs, and igniting the spirit of discovery throughout the community of Scripps physicians-in-training and the pre-doctoral scientists who have a keen interest to pursue a career in molecular medicine.